FDA Panel Flubbed in Arena’s Lorcaserin Disapproval

Last week’s FDA panel that voted 9-to-5 against approving Arena Pharmaceuticals’ (NASDAQ:ARNA) obesity drug Lorqess (lorcaserin) apparently blundered in its assessment that the company’s rat breast tumor findings merit concern, according to the FDA’s own published standards.

Bloomberg reported that "a panel of outside advisers to the FDA voted against recommending the drug for approval, citing concerns about tumors seen in rats in early-stage testing of the drug. … Of particular concern was the increase of mammary tumors in rats treated with lorcaserin, the committee said."

Lorcaserin was investigated in a standard battery of genotoxicity, reproductive toxicity, general toxicity, and carcinogenicity studies. Lorcaserin showed no reproductive toxicity or genotoxicity. General toxicity studies were conducted in mice, rats, and monkeys at doses that produced very high exposure multiples relative to the human maximum recommended dose (NASDAQ:MRD). In repeated dose Good Laboratory Practice (NYSE:GLP) toxicity studies, lorcaserin was generally well tolerated at doses below the maximum tolerated dose (NYSE:MTD) in all three species and there appeared to be no adverse findings of direct relevance to humans at therapeutic doses [emphasis added].

Two-year carcinogenicity studies were conducted in mice and rats. There was no evidence of carcinogenicity in mice. In rats, and almost exclusively male rats, tumors were found in multiple organs primarily at the highest dose, which provided an exposure that was 56-fold greater than human and was clearly above the MTD[emphasis added].

So lorcaserin was found not to be genotoxic, meaning it does not harm a cell’s genetic material, especially DNA.Rather, lorcaserin’s mechanism for promoting breast tumors at only high, toxic doses may be hormonal, in a way that apparently does not exist in humans.According to the FDA brief, “The mammary tumors are attributable to increased prolactin, a mechanism peculiar to the rat.”

[T]he relevance of these tumors to humans is questionable because: 1) lorcaserin is not genotoxic; 2) substantial margins and/or rodent specific mechanisms were identified for each of the tumors; 3) the tumors were found primarily in one gender of one species at a toxic dose; and 4) no preneoplastic or neoplastic lesions were found in any other toxicity studies in the rat, mouse or monkey.

Rat tumors, benign and malignant

Male rats had a significant benign breast tumor (fibroadenoma) incidence only if they received 56 times the lorcaserin exposure humans would get at the proven-effective dose of 20 mg per day.

Male rats had no significant increase in breast cancer (adenocarcinoma) at any dose of lorcaserin.

Female control rats, who received no lorcaserin, showed high rates of spontaneous benign and malignantbreast tumors at baseline. Forty-three percent of female rats that never touched lorcaserin developed cancer! That's just how these animals' bodies operate.

Female rats developed significantly more benignbreast tumors (fibroadenomas) at all doses of lorcaserin, but this has no known implication for human cancers.

Female rats showed a significant increase in breast cancer (adenocarcinoma) only if they received 84 times the lorcaserin exposure humans would get at the standard dose of 20 mg per day.

It has been agreed that if a drug is only positive [for a cancer association] in rodents at doses above those producing a 25-­fold exposure over exposure in humans, such a finding would not be considered likely to reflect a relevant risk to humans.

Arena found a significant benign tumor rate in male rats exposed to no less than 56-fold amounts of lorcaserin compared to what humans would receive, and a significantly increased cancer rate in female rats exposed to no less than 84-fold amounts. These dosages are well above the FDA threshold of "25-­fold exposure over exposure in humans."Therefore, "such a finding would not be considered likely to reflect a relevant risk to humans," according to the FDA’s prior, considered scientific findings and advice to pharmaceutical manufacturers.

No wonder Arena CEO Jack Lief said in a conference call with analysts last Friday that it was a “shame” there were no experts in carcinogenesis or toxicology on the panel.

"My view is they were having difficulty understanding the presentation," he said.

[FDA panelist] Edward Gregg, chief of epidemiology and statistics in the Centers for Disease Control and Prevention's Division of Diabetes Translation, said he was "spooked" by the rat study tumor results.

Many on the panel of metabolic and endocrinology experts, however, acknowledged that their particular expertise was not in cancer, and therefore, had difficulty interpreting the rat study results. ...

Given the potential for lorcaserin to be used by hundreds of thousands of women once it enters the U.S. market, "there is just too much uncertainty" without more studies to answer the tumor question, said [FDA] panelist Jacqueline Gardner, a professor of pharmacy at the University of Washington.

What is the uncertainty to which pharmacist Gardner refers?Could it be based on some panelists’ difficulty in interpreting Arena’s data, or in determining its applicability to humans in accordance with cancer biology principles?

Panelist Michael Proschan, a mathematical statistician at the National Institute of Allergy and Infectious Diseases, seemed honest about his perception of the rat tumor data. "I feel totally lost," he said. "I have no idea how to translate from animals to people."

Lorcaserin may play an important role not just in weight loss, but also in treating complications of obesity.According to the FDA brief, “Lorcaserin 10 mg BID caused significant improvements in blood pressure, lipid profiles, and insulin resistance in parallel with weight loss.”

In a July 2010 New England Journal of Medicine editorial, obesity expert Arne Astrup, MD, wrote, “The justification for using lorcaserin to manage obesity is not greater efficacy than currently available drugs [orlistat (Xenical by Roche (OTCQX:RHHBY) and Alli by GlaxoSmithKline (NYSE:GSK)), and sibutramine (Meridia by Abbott Laboratories (NYSE:ABT))], but rather an apparently much better safety and adverse-event profile and very clear-cut beneficial effects on risk factors for type 2 diabetes and cardiovascular disease.”

The FDA owes the public a commitment to competent scientific evaluation in its drug-approval decisions.It should act consistently with its prior scientific findings and industry guidance, promptly overrule the lorcaserin panel's mistaken vote, and set the record straight on lorcaserin’s cancer safety findings.